The long-term goal of this research program is the chemical synthesis of certain naturally occurring nitrogen-containing systems (alkaloids) which exhibit potentially desirable biological properties and which may eventually lead to therapeutic agents of value in the treatment of human diseases. The objective in all cases is a synthesis of the naturally occurring enantiomer of an alkaloid in sufficient quantity to enable evaluation of its pharmacological properties to be conducted. The focus for the next grant period will be on the asymmetric synthesis of five alkaloids, each representing a different structural class. Halichlorine, an alkaloid which inhibits induction of vascular cell adhesion "molecule-1 (VCAM-1), is considered to be an important lead compound for treatment of atherosclerosis and coronary artery diseases. The synthesis of this target will be approached using a transannular cycloaddition of a nitrone to construct the spiroindolizidine core of the alkaloid. A second target is gymnodimine, an alkaloid associated with neurotoxic shellfish poisoning. Synthesis of this alkaloid, for which new methodology is proposed for constructing the azaspirocyclic core, is intended to assist investigation of the mechanism by which it manifests neurotoxicity. Koumine, an alkaloid of the toxic Gelsemium family, is of interest on account of its extensive lore as a therapy in Chinese traditional medicine. An approach to koumine is proposed which makes use of a recently discovered photochemical synthesis of perhydroisoquinolines, and which creates the polycyclic framework of koumine from this platform. A fourth target, huperzine A, also has its roots in Chinese traditional medicine where it is used as a therapy for cognitive disorders. Now recognized as a potent inhibitor of the enzyme acetylchloinesterase, huperzine A is a valuable lead compound in the search for substances capable of alleviating symptoms of Alzheimer's dementia. A synthesis of huperzine A is proposed which employs a unique rearrangement to construct the bicyclo[3.3.1]nonene core of this molecule. A final target, the alkaloid nomofungin, is a cytotoxic substance that, unfortunately, is no longer available from its natural source in Hawaii. A plan is presented for the synthesis of this complex heptacyclic molecule which envisions a thio-Claisen rearrangement as the key step for building the vicinal quaternary carbons of this structure.